The metabolic syndrome, which affects more than 25% of adults in the United States, is associated with cardiovascular disease and a dyslipidemia that includes increased serum triglycerides and low levels of high density lipoprotein (HDL). HDL protects against atherosclerosis by promoting the removal of excess cholesterol from the body, and by carrying proteins that protect against inflammation. The metabolic syndrome is a complex disorder in which some branches of the insulin signaling cascade become resistant to insulin, whereas others remain sensitive. Superimposed upon these changes are the direct effects of dietary factors. Dissecting the roles of the different branches of the insulin signaling pathway and dietary factors in producing dyslipidemia and atherosclerosis is an important step towards preventing cardiovascular disease. The specific goal of this application is to determine how the different branches of the insulin-signaling pathway control HDL and sterol regulatory element binding protein (SREBP)-1c, a nuclear transcription factor which regulates serum triglycerides. The central hypothesis is that insulin resistance downstream of Akt leads to pro-atherogenic changes in HDL, whereas continued sensitivity in other branches of the insulin signaling cascade is required for activation of SREBP-1c. To test this hypothesis, we will (1) determine whether signaling through the insulin receptor is necessary for activation of SREBP-1c in the metabolic syndrome by subjecting mice deficient in hepatic insulin signaling to high fat feeding;(2) determine the branch of insulin signaling that regulates HDL by measuring HDL clearance and expression of the enzymes involved in HDL metabolism in mice deficient in all hepatic insulin signaling and mice deficient only in hepatic signaling through Akt;and (3) determine whether hepatic insulin resistance decreases the atheroprotective proteins associated with HDL using mass spectroscopy. These studies will identify urgently needed targets for reversing the dyslipidemia of the metabolic syndrome.